Chronic heart failure (CHF) is associated with considerable morbidity and mortality despite recent advances in heart treatments. There are a number of aetiological conditions that ultimately result in chronic heart failure including coronary artery disease, different cardiomyopathies, hypertension, or valvular diseases. A detailed characterization of chronic heart failure as a clinical syndrome may be found in Hunt S A, Baker D W, Chin M H, Cinquegrani M P, Feldman A M, Francis G S, Ganiats T G, Goldstein S, Gregoratos G, Jessup M L, Noble R J, Packer M, Silver M A, Stevenson L W. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). 2001. American College of Cardiology (http://www.acc.org/clinical/guidelines/failure/hf_index.htm).
Coronary artery disease (obstruction or blockage of the arteries of the heart) leads to ischaemia; this is characterised by a lack of blood supply to tissues; in this case the heart. This lack of this essential oxygen and nutrients can result in the tissue becoming impaired or permanently damaged. Once damaged the cardiac tissue is unable to perform its function. As such, the strength and efficiency of the heart muscle is reduced (this is technically termed left ventricular systolic dysfunction and results in a reduced ejection fraction; a measure of the pumping capacity of the heart). In addition to its ability to damage the heart muscle; cardiac ischaemia is frequently though not invariably identified by the physical symptom of angina (in some cases—ischaemia may occur without the correlate of anginal chest pain). Angina typically occurs under circumstances that would be expected to increase the hearts workload; resulting in an increased requirement for energy. This increased energy requirement necessitates increased oxygen provision that cannot be provided in the presence of arterial blockage; causing relative ischaemia and hence pain. Exercise is a good example of this, where the output of the heart is increased but the blood supply does not match this increase in performance and thus some of the heart tissue becomes ischaemic resulting in pain. This ischaemia, despite causing pain need not invariably result in irreversible heart damage and is not invariably related to pump dysfunction. Although ischaemia can cause both angina and heart failure, the exact manifestation of ischaemia relates to its severity and time course. Ultimately ischaemia as an inciting influence for heart failure is dissociable from its capacity to cause angina; they may or may not co-exist.
However, a lack of blood supply is only one of the many causes for cardiac pump impairment. Other reasons include cardiac arrhythmias (abnormal heart electrical rhythms), hypertension (high blood pressure), valve diseases, infections, toxins or impairment in the nervous stimulation of the heart to name but a few.
While these initial insults to the heart are diverse in character and severity, their common feature is that they cause either damage to heart muscle cells (myocytes) or at least impair their ability to contract. This results in left ventricular systolic dysfunction. It is this common feature that triggers the cascade that results in the stereotyped and distinct state of chronic heart failure. As discussed in “Mechanisms and Models in Heart Failure: A Combinatorial Approach”, by Douglas L. Mann, M D, Circulation, 1999; pages 999-1008 and in “Drug Therapy: The Management of Chronic Heart Failure”, by Jay N. Cohn, M D, New England Journal of Medicine 1996; pages 490-498), heart failure may be viewed as a progressive disorder that is initiated after an index event either damages the heart muscle, with a resultant loss of functioning cardiac myocytes, or alternatively disrupts the ability of the myocardium to generate force, thereby preventing the heart from contracting normally. This index event may have an abrupt onset, as in the case of a myocardial infarction (heart attack), it may have a gradual or insidious onset, as in the case hemodynamic pressure or volume overloading, or it may be hereditary, as in the case of many of the genetic cardiomyopathies.
Regardless and irrespective of the diverse nature of the inciting event, the feature that is common to all of these index events is that they all, in some manner, produce a decline in pumping capacity of the heart. Following the initial decline in pumping capacity of the heart, acutely, patients may become very symptomatic; they may be minimally symptomatic or may even remain asymptomatic. However, the decreased pump capacity generally results in a diminished cardiac output. This chronically activates the neurohumoral system, particularly the sympathetic nervous system, the renin-angiotensin-aldosterone system, and potentiates the release of vasopressin.
Although in the short term these adaptations are beneficial due to their capacity to maintain blood flow to vital organs; in the long term, these reflexes have deleterious effects and ultimately result in cardiac remodelling (FIG. 1). This remodelling is the central stereotyped feature of CHF irrespective of the inciting influence and is manifest at the macroscopic level (visible to the eye) by dilatation of the heart chambers. However there is also corresponding remodelling at the molecular and the cellular level. These include changes in cellular transcription (the genetic programmes determining cellular function) and the resulting cellular pathways. One aspect of cellular function that is altered in chronic heart failure is cellular metabolism and energy production.
The common unified programme of the failing heart irrespective of the inciting insult thus includes chronic energy starvation. It has been postulated that these energy changes are not simply just a feature of CHF but are of mechanistic importance in chronic heart failure. The failing heart is characterized by a marked change in substrate preference away from fatty acid metabolism toward glucose metabolism. Glucose is a more efficient cellular fuel and this particular adaptation may therefore be an adaptive feature of chronic heart failure—partially mitigating the effect of energy deficit. It therefore follows that augmentation of “metabolic remodelling” is a potential target in chronic heart failure; however to date there has been a paucity of even animal data to confirm this assertion.
Perhexiline (2-(2,2-dicyclohexylethyl)piperidine) is a known anti-anginal agent that operates principally by virtue of its ability to shift metabolism in the heart from free fatty acid metabolism to glucose, which is more energy efficient. Aside from being used for the treatment of angina as a manifestation of ischaemia (in patients who may or may not coincidentally have heart failure), there is no record of using perhexiline to treat instances of non-ischaemia and certainly no known use of this drug to treat instances of heart failure independent of angina. Phrased alternatively; while perhexiline has been used to treat patients with angina and ischaemia at the point where this may be an inciting influence for heart failure as demonstrated by arrow (a) in FIG. 1, (which therefore may or may not be associated with active ischaemia-related pump dysfunction or ischaemia-related congestive cardiomyopathy); there has never been a suggestion that perhexiline may be useful in the modification of chronic metabolic remodelling in the distinct stereotyped phenotype of chronic heart failure as demonstrated by arrow (b) in FIG. 1.
With further reference to FIG. 1, it is apparent that there is an inciting phase of heart failure, which is due to diverse initiating influences. While completely unrelated to one another, these diverse influences all result in pump failure and left ventricular systolic dysfunction. Irrespective of inciting influence, this pump failure initiates an initially adaptive but ultimately partially maladaptive remodelling. This chronic remodelling is a stereotyped molecular, cellular and macroscopic phenomenon, and the central cause of eventual progressive chronic heart failure. Chronic heart failure remodelling ultimately leads to a vicious cycle of detrimental events. Part of the chronic heart failure phenotype is energetic deficiency and a shift in cellular metabolism away from fatty acid metabolism to glucose metabolism.